European Heart Journal (2013) 34, 1767–1771
doi:10.1093/eurheartj/eht164
Sensible guidelines for clinical trials: are current
European regulations ‘a gift to America’?
While the European Commission tries to rewrite the regulations for
conducting clinical trials, some academics under the umbrella of the
Sensible Guidelines Group are taking matters into their own hands and
urging a return to the basic principles of randomized clinical trials,
reports Barry Shurlock PhD, in conversation with Prof. Sir Rory Collins,
Oxford University, UK
Sir Rory Collins
It is widely accepted that the pharmaceutical industry is in a difficult
place. As many blockbuster products reach the end of their patent
protection and CEOs stare down near-empty product pipelines,
investigators are racking their brains for the reasons for this
unhappy situation. Some argue that it is necessary to find new pathways, while others believe that equally important is a reform of the
regulations imposed on clinical investigators. These have become
so complex, it is argued, that they unnecessarily inflate costs, but
worse than that, they impugn patient safety and act as a wholesale
dampener on the whole business. Companies are loathe to ‘place
as many bets’ on promising new compounds, researchers are demoralized and demotivated by the sheer bureaucracy of the system, and
innovation is crushed.
Within the European Union, clinical trials are currently governed
by Directive 2001/20/EC, issued on 4 April 2001. This was subsequently interpreted and set into law by each member country,
thereby having the perverse effect of making it harder to carry out
multi-national studies. Its other failings—now accepted even by the
EU Commission itself—are that it has hugely increased costs, lengthened delays, and imposed a huge bureaucratic burden on clinical
researchers. It is hardly surprising, therefore, that the number of
applications for new clinical trials between 2007 and 2011 fell by
25%. To repair the situation, in July 2012, following a public consultation, the Commission proposed a single Regulation that would apply
to all member states (Directive 2001/20/EC/2012/0192). Although
many researchers accept that the new proposals have some benefits—such as a single portal for authorization of new trials, rather
than country by country applications; more flexibility for consent in
emergencies; and lower costs of indemnity—they fall well short of
what is required, and even fail to appreciate the basic principles of
randomized controlled trials.
These are the views of Prof. Sir Rory Collins MB BS, FRCP, F Med
Sci, Co-Director of the Clinical Trial Service Unit and Epidemiological
Studies Unit, Oxford University, UK, which has joined with other
groups from McMaster University, Canada, and Duke University,
USA, to form the Sensible Guidelines Group (SGG). Following meetings in Washington, Oxford, and Toronto (with another anticipated
in China), some of the most experienced clinical trials academics in
the world have reached a consensus on the way forward to rid clinical
trials of undue bureaucracy, maximize patient safety, and generally
improve the efficiency of reaching valid conclusions from large multicentre randomized studies.
Among a raft of SGG proposals is a risk-based approach to trials of
drugs that are well understood, such as testing a new use for a marketed
product with a good safety profile. More central monitoring in multicentre trials is also advocated, with less emphasis on site visit monitoring, which researchers at Duke University have estimated accounts for
one-third of the total costs of a typical industry trial—perhaps as much
E100–150 million. And yet, according to Collins, there is no evidence
that ‘all that hopping on planes’ is effective or cost-effective.
He said: ‘Huge effort is put into checking that data points are correct,
whereas this is not required – in a randomized controlled trial you
don’t need accurate data as much as you need a lack of bias between
the treatment and control groups. In fact, with the Heart Protection
Study of simvastatin, we compared the results with both adjudicated
and non-adjudicated data and there was no difference. We need to
focus more on reliable results, not accurate data!’
Another area where current regulation is ineffective, SGG
believes, is the insistence that investigators report every suspected
unexpected serious adverse reaction (SUSAR) on a case-by-case
basis. He said: ‘Regulators are being swamped by these reports,
absorbing a huge expenditure of money and effort, and yet such an
approach to pharmacovigilance in trials has rarely improved patient
safety. It may detect large increases in rare events, but it is not effective
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
1768
in detecting more important – from a public health perspective –
moderate increases in common serious outcomes. For example, the
increased mortality with torcetrapib was not detected by the reporting
of SUSARs. Instead, it was detected through ongoing review in the trial
by an independent data monitoring committee of the incidence of
Serious Adverse Events (SAEs) in the treatment versus control
groups. In the recent THRIVE trial comparing niacin versus placebo
in more than 25,000 patients, we found an excess event rate of 30
SAEs – such as haemorrhagic stroke, infections and new-onset diabetes – per 1000 patientstreated with niacin for 4 years. This was
for a drug which has been used for 50 years and costs more than a
billion dollars in prescription each year in the US alone. And yet,
neither pharmacovigilance during that whole period, nor SARs reporting in THRIVE, detected these serious hazards!’
According to SGG, many defects of current regulation can be
traced to the activities of the International Conference on Harmonisation – Good Clinical Practice (ICH-GCP), a well-established
‘ethical and scientific quality standard’. It was developed by the
pharmaceutical industry and regulatory authorities in order to harmonize regulatory practice across the EU, the USA, and Japan. Unfortunately, although ICH-GCP is well-intentioned, SGG believes that it
has proved too difficult to interpret—with regulators sometimes
CardioPulse
needing to issue hundreds of pages of advice. Also it is not based
on a sound understanding of clinical trial methodology, particularly
the ability to get valid results from data that are not complete and
not entirely accurate, provided the treatment and control groups
are similarly affected. Collins said: ‘One of the problems with
ICH-GCP is that it’s difficult, if not impossible, to get responses to
our concerns from the committee. It may be necessary for academic
researchers to work with the FDA and EMA to develop another,
better informed standard’.
Many of the proposals of the SGG are in line with the US Clinical
Trials Transformation Initiative, especially its views on safety, which
have been recognized by the FDA and incorporated in revised safety
reporting requirements (www.fda.gov; Sherman et al., N Engl J Med
2011;365:3–5). However, SGG believes that the draft EU regulation
has failed to address the main problems adequately. Collins said:
‘What’s needed is to go back to first principles and recognize the
strengths of having randomization and control groups in trials. The
current regulations don’t do that and consequently, are fundamentally
flawed. We are a long way from where we need to be. Current regulations have led to fewer trials and less reliable evidence and consequently, reduced patient safety. One FDA official even dubbed the current
EU Clinical Trials Directive ‘Europe’s gift to American research’!’
Creeping epidemic of obesity hits Asia Pacific
region
Overeating replaces under-nutrition, as cardiologists call for policies
to make healthy choices easier
spending too much time on the internet and mobile devices so they
don’t take up physical activity. The Asian culture revolves around
food as a way of showing hospitality because in the past there was a
lot of famine. As a result there is a cultural perception that if you’re
not fat or obese then you are not well off’.
The Asia Pacific Cohort Studies Collaboration (APCSC) found
that the prevalence of overweight and obesity among 14 countries
in the Asia Pacific region varied considerably by country. In men incidence of obesity (BMI .30 k/m2) ranged from 0.3% in India and 1.3%
in Indonesia to 13.8% in Mongolia, and 19.3% in Australia. In women,
the lowest rates were found in India (0.6%), China and Japan (both
3.4%) and the highest rates in Australia (22.2%) and Mongolia (24.6%).
Experts from the European Society of Cardiology (ESC) led a one
day collaborative programme on prevention at the 19th Asia Pacific
Congress of Cardiology held on 21 –24 February 2013 in Thailand.
Overeating, sedentary lifestyles, cultural attitudes, and lack of
prevention programmes are to blame for the rising epidemic of
obesity in the Asia Pacific region. Overweight and obesity has
quadrupled in China and societies still label people of healthy
weight as undernourished.
Prof. Kui-Hian Sim, President Elect of the Asian Pacific Society of
Cardiology, said: ‘In many of the countries in Asia Pacific the malnutrition problem nowadays is not under-nutrition it is over-nutrition,
which has resulted in overweight and obesity’. He added: ‘Asia Pacific
has developed rapidly and technological advances result in children
But Dr Rachel Huxley (Minneapolis, MN,
USA), APCSC co-investigator, said: ‘Although
the absolute prevalence of obesity in
Australia was considerably higher than that of
China and Japan, the relative increases over
the last 20 years, has been much greater in
these two Asian countries than in Australia’.
The combined prevalence of overweight and obesity increased by:
† 46% in Japan from 16.7% in 1976–1980 to 24% in 2000.
† 414% in China from 3.7% in 1982 to 19% in 2002.
1769
CardioPulse
The APCSC researchers also calculated that overweight and obesity
accounted for:
† Almost 8% of coronary heart disease in Mongolia and .9% in
Australia.
† Almost 9% of ischaemic stroke in Mongolia and .10% in Australia.
Dr Huxley said: ‘Increasing ‘Westernisation’ of lower- and
middle-income countries in the Asia Pacific region is associated
with increasing gross domestic product (GDP) and the adoption of
more Westernized patterns of physical inactivity and diets richer in
calories and fat. The influx of fast food, confectionary and soft
drink companies into the region is likely to further exacerbate the
obesity problem. In high income countries there is an inverse association between income/education with obesity, whereas in lowermiddle income countries the reverse is more commonly found’.
The longest on-going cardiovascular epidemiological study in India
found that more education was significantly associated with an increase
in overweight. The authors concluded: ‘The process of disease transition has started in the Indian middle class and a decline fuelled by socioeconomic changes and increasing education is inevitable in this group’.
Dr Huxley said: ‘Strategies should focus on the food environment
(making healthy food choices the easiest and cheapest option) and
the physical environment to promote incidental physical activity (e.g.
using stairs instead of lifts and increasing the walkability in towns and
cities) as well as leisure time physical activity. In addition, there are a
number of policy areas that could influence the food environment
such as mandatory use of food labelling, higher taxes on high fat/
energy foods, restricted advertising on fast food (especially to children)
and food subsidies for fruits and vegetables’. The ESC advocates such
regulations, particularly when lifestyle changes have not worked.
Panos Vardas (credit Sam C. Rogers)
Prof. Panos Vardas, ESC President, commented: ‘The 2012 European
Prevention Guidelines state that 80 –90% of all cardiovascular disease
is preventable. Politicians and health professionals in the Asia Pacific
region need to do more to make the healthy choice the easy choice,
to avoid the high rates of obesity increasing even further’.
Prof. Sim concluded: ‘Very little has been done about overweight
and obesity in the Asia Pacific region because it doesn’t belong to any
specialty. Cardiologists focus on smoking and risk stratification while
diabetologists look at blood sugar. Cardiologists need to take up the
challenge of obesity in order to curb the cardiovascular epidemic’.
Andros Tofield
CardioPulse Survey series: Italy
Strengths and limitations of the health-care system
of Italy
Roberto Ferrari MD FESC takes part in our survey on behalf of Italy
Roberto Ferrari
What is the greatest strength of Italy’s health system in tackling cardiovascular disease (e.g. prevention, acute treatment, long-term
treatment)?
The greatest strength is that Italy provides universal health care to
the entire population.
In 2000, the World Health Organization (WHO) released the
World Health Report 2000 ranking the world’s best health-care
systems. Italy was ranked second, after France. The Servizio Sanitario
Nazionale works on the following principles: every individual has to
be treated with equal dignity and have equal rights regardless of personal characteristics and their role in society, with access to health care and
available resources to meet their primary health care needs. Individual
health has to be protected with appropriate preventive measures and
interventions. Available resources have to be primarily allocated to
support groups of people, individuals and certain diseases that are socially, clinically, and epidemiologically important. Priority is given to
interventions that offer greater efficacy in relation to costs.
What is its biggest weakness?
The health system encountered a number of financial problems from
its beginning in 1978. First, there was very little coordination of
health-care services at a national level and no financial controls.
The authority to spend rested with the local health units, but the
1770
responsibility to pay was still with the State. The result was continuous growth in expenditure and huge budget overspends. There have
been a number of reforms since the early 1990s including on by which
each citizen can choose their health-care provider. Payments have
also been regulated using a Diagnostic Related Group system and
Managers have been placed on fixed contracts with regular performance reviews.
Apart from these economic weaknesses, in my opinion, another
important area that needs to be addressed is the link between
hospital care and general practitioner (GP) care. This is particularly important for chronic pathologies such as myocardial ischaemia
and heart failure. Often, efforts to provide the best possible hospital treatment in terms of intervention or drug therapy is not necessarily followed up by the GP and this causes difficulties for the
patients.
What is being done to measure and
improve quality in cardiovascular
disease?
Italy has two official cardiovascular societies—the Italian Society of
Cardiology (SIC) and the National Association of Cardiology
Doctors (ANMCO). Both have conducted several national registries
in order to measure and to improve the quality of cardiovascular care
provided to the general public. Of significance is the BRING-IN
project, conducted by ANMCO. After reviewing registry results,
ANMCO noted that calcium antagonists were used in 40% of the
population with congestive heart failure and beta-blockers were
only used in 5%. The BRING-IN project asked all of the registry participants why beta-blockers were not being used when they were the
recommended therapy in the European Society of Cardiology Guidelines. This resulted in an increase in the use of beta-blockers and a
decline in the use of calcium antagonists.
What is being done to control costs?
Current Italian health-care expenditure is 9% of the GDP, up from 5%
in 1980. Besides the over-expenditure, the Italian government faces
major problems over the next 30 years. The shrinking working population will produce less tax revenue. This is worsened in the short
term by a slow economy. Reforms are aimed at reducing expenditure
and improving planning. Regions that overspend are subject to automatic increases in regional taxation.
Recent reforms provide several measures to control costs. The
first reform relates to the closure of smaller, regional hospitals.
These would be substituted by emergency points of care and consultation. Another area of control is a revision of drug and device expenditure. In many regions in Italy, GPs are encouraged to use, whenever
possible, generic drugs, and devices are bought centrally by the region
and distributed to the hospitals. This means that the region can negotiate better pricing.
CardioPulse
How does Italy address
cardiovascular preventive services?
The Italian Government and particularly the Istituto Superiore di
Sanità is very much involved in prevention. There are several
on-going projects and numerous financial grants have been issued.
The real problem is that prevention should be tackled not just by
the cardiologist or indeed the medical profession alone but rather
by the government. The situation is currently jeopardized by disparity
in the quality of health care: good services in some areas (Veneto and
Emilia Romagna) and inefficient in other areas.
Of note, Italy was the first European country to approve the ban on
smoking, which has been linked to the decline of cardiovascular mortality.
How are cardiologists in Italy
incorporating innovative drugs and
devices (e.g., TAVI) into their
practice?
Cardiologists are usually very enthusiastic regarding innovative drugs
and devices. However, there is a cost issue involved here too. It is
often the case that TAVIs, for example, are performed at larger hospitals which act as a hub while the smaller hospitals are the spokes. Of
significance is the fact that, the Italian Pharmaceutical Agency (AIFA)
is very conservative regarding the approval of new drugs as more
interest causes increased expenditure.
What is the greatest challenge
facing medicine in Italy over the
next decade?
The main challenge for the future is the ageing population. A better
environment and improved medical techniques have both resulted in
people living longer. The ageing population will require new facilities
to deal with the physical and mental diseases associated with old age
as well as an increase in nursing homes to deal with end-of-life care.
The options available to the Italian government are few if they wish
to maintain current health-care standards. The working population
can be increased through immigration and raising the retirement
age. Overall, taxation will need to be increased. Private health-care
expenditure may also rise, to pay for services which the government
can no longer afford.
Italy will need to provide a national network of hospitals and
general practitioners in cardiac care able to compete in terms of
quality and cost with other European countries once national barriers are eliminated.
Roberto Ferrari MD FESC, [email protected]
1771
CardioPulse
Insomnia linked to increased risk of heart failure
People who suffer from insomnia appear to have an increased risk of
developing heart failure, according to the largest study to investigate
the link
The study, published online on 6 March 2013 in the European Heart
Journal1, followed 54 279 people between the ages of 20– 89 for an
average of .11 years, and found that those who suffered from
three symptoms of insomnia had a more than three-fold increased
risk of developing heart failure compared with those with no insomnia symptoms.
Dr Lars E. Laugsand, a post-doctoral fellow in
the Department of Public Health,
Norwegian University of Science and
Technology, Trondheim, Norway, said: ‘We
related heart failure risk to 3 major
insomnia symptoms including trouble falling
asleep, problems staying asleep, and not
waking up feeling refreshed in the morning.
In our study, we found that persons
suffering from insomnia have increased risk
of having heart failure. Those reporting suffering from all 3
insomnia symptoms simultaneously were at considerably higher
risk than those who had no symptoms or only one or two symptoms’.
However, he stressed that although the study shows that insomnia is
linked to an increased risk of heart failure, it does not show that it
causes it. ‘We do not know whether heart failure is really caused
by insomnia, but if it is, insomnia is a potentially treatable condition
using strategies such as following simple recommendations concerning sleeping habits (often referred to as sleep hygiene), and several
psychological and pharmacological therapies. Evaluation of sleep problems might provide additional information that could be used in prevention of heart failure’.
He said further research would be required to establish whether
or not insomnia caused the condition. ‘It is still unclear why insomnia
is linked to higher heart failure risk. We have some indications that
there might be a biological cause, and one possible explanation
could be that insomnia activates stress responses in the body that
could negatively affect heart function. However, further research is
also needed to find the possible mechanisms for this association’.
Dr Laugsand and his colleagues collected data from men and
women enrolled in the Nord-Trondelag Health study (HUNT)
between 1995 and 1997 and who were free from heart failure
when they joined. The researchers followed the study participants
until 2008, by which time there had been a total of 1412 cases of
heart failure.
When participants joined the study, they were asked whether they
had difficulty going to sleep and staying asleep, with the possible
answers being ‘never’, ‘occasionally’, ‘often’, and ‘almost every night’.
They were also asked how often they woke up in the morning not
feeling refreshed (non-restorative sleep), with the replies being
‘never, a few times a year’, ‘one to two times per month’, ‘once a
week’, ‘more than once a week’.
After adjusting for factors that could affect the results, such as age,
sex, marital status, education, shift work, blood pressure, cholesterol,
diabetes, body mass index, physical activity, smoking, alcohol, any
previous heart attack, depression, and anxiety, the researchers
found that having difficulties going to sleep and staying asleep
almost every night, and having non-restorative sleep more than
once a week were associated with an increased risk of heart failure
when compared with people who never or rarely suffered from
these symptoms. There was a trend showing a link between the frequency of the symptoms and an increased risk, although most of these
findings did not reach statistical significance.
When they looked at the number of symptoms, the researchers
found a statistically significant three-fold (353%) increased risk of
heart failure for people who had all three insomnia symptoms, compared with those with none, after adjusting for most confounding
factors apart from depression and anxiety. When they adjusted
their findings to include depression and anxiety, the risk was even
more significant, with a slightly more than four-fold risk (425%) of
heart failure.
The authors write in their paper: ‘We found a moderate risk increase related to the individual insomnia symptoms. However, the
risk among those with all the three insomnia symptoms simultaneously was particularly high even after adjustment for established cardiovascular risk factors and psychological distress. This finding may be
interpreted as suggesting that compromising some aspects of sleep
may be somehow compensated for, and the net effect on cardiovascular disease may be limited. For example, having difficulty falling
asleep might be compensated for by a satisfactory depth and a
good continuity of sleep. However, if the initiation of sleep is poor
and combined with repeated awakenings and superficial sleep,
there may not be any compensatory mechanisms’.
Andros Tofield
ESC Press Office
Reference
1. Laugsand LE, Strand LB, Platou C, Vatten LJ, Janszky I. Insomnia and the risk of incident
heart failure: a population study. Eur Heart J; doi:10.1093/eurheartj/eht019. Published
online ahead of print 15 March 2013.
CardioPulse contact: Andros Tofield, Managing Editor. Email: [email protected]